Trauma and Genomics Modulate Brain Structure across Common Psychiatric Disorders

摘要

ABSTRACT Exposure to trauma and abuse during childhood, a critical neurodevelopmental period, is a major risk factor for adult psychopathology. However, not all children exposed to childhood trauma will develop adult psychopathology. Variability in the risk for trauma-related pathology is expected to arise in part from genetic susceptibility. Several genes have recently been identified that interact with childhood trauma to increase rates of anxiety and mood disorders in adulthood. This risk can be more easily detected by examining endophenotypes such as brain measures obtained from MRI because of a simpler underlying genetic architecture with fewer individual genes or pathways than the multiple factors driving overall risk for psychopathology. Understanding the molecular-genetic contributors to brain structure that conspire with early-life environment (psychological trauma) and lead to adult psychopathology, will require large-scale collaborative efforts which harness big-data methodologies. Our goal is to conduct a GWAS of relevant structural brain measures in individuals exposed to childhood trauma, with the long-term goal of identifying genetic modulators of brain structure that are informative for early prediction and treatment for a range of psychiatric disorders where childhood trauma is a major risk factor. We hypothesize that (1) childhood trauma will interact with specific genetic markers to produce structural brain alterations and adult psychopathology, (2) that unique genetic variants, in the context of genetic vulnerability to childhood trauma, will influence the onset of specific disorders (e.g. depression vs PTSD), as well as (3) the presentation of specific symptom constructs (e.g. sustained threat) across disorders. Finding disease-associated genetic variation that point to molecular mechanisms of pathogenesis has proven challenging due to the polygenicity of clinical phenotypes. Leveraging neuroimaging phenotypes may offer a more direct path than clinical phenotypes in identifying these elusive genetic markers and relevant neurobiological pathways. Ultimately, the promise of finding genetic contributors of any psychiatric disorder is in identifying the presence of new biologic pathways for which targeted interventions may be devised and deployed.